The potential for relapse following cessation of drug use can last for years, implying the induction of stable changes in neural circuitry. In hippocampal slices from rats treated with nicotine for 1 week, withdrawal from nicotine in vivo produces an increase in CA1 pyramidal cell excitability that persists up to 9 months. Immediately upon drug cessation, the enhanced excitability depends on input from regions upstream of CA1, while the long-term excitability change (> 4 weeks) is expressed as an increase in the intrinsic excitability of CA1 neurons. Re-exposure to nicotine in vitro restores hippocampal function to control levels via activation of high-affinity nicotinic acetyl-choline receptors after1dof withdrawal, but not at times>4 weeks. Thus, nicotine in vivo first induces homeostatic adaptations followed by other more robust neural changes. These mechanisms may contribute to hippocampal localized cue-motivated reinstatement of drug-seeking and/or cognitive deficits observed during withdrawal. Copyright © 2011 the authors.